Obesity is a common preventable cause of morbidity and mortality, and ethnic minorities, independent of socioeconomic status, are disproportionately affected. Genetic and environmental factors are known to be important in the development of obesity, yet the interactions between polymorphic variants within genes and environmental risk factors are poorly understood despite their fundamental importance. Our preliminary data demonstrate that central body fat is common among Yup'ik Eskimos, an "at risk" and underserved population in Southwest Alaska. The objective of this revised application is to investigate whether selected gene- environment interactions are risk factors for obesity in Yup'ik Eskimos. Obesity genome linkage scans have implicated the following chromosomal regions in multiple independent studies, including a 10cM genome sub-scan we conducted in Yup'ik Eskimos: 2p, 3q, 5p, 6p, 7q, 10q, 11q, 17p and 20q. We searched for biologically plausible candidate genes in these regions and prioritized seven genes for exhaustive genetic investigation: adiponectin (3q27), AMP kinase gamma 2 subunit and nuclear respiratory factor-1 (7q36), stearoyl CoA desaturase (10q23), sterol regulatory element binding protein (17p11), insulin sensitive glucose transporter (17p13), and hepatocyte nuclear factor 4 alpha (20q12). These genes and their encoded proteins are regulated by polyunsaturated fatty acids (PUFAs) and physical activity, and several code for transcription factors involved in adiponectin expression. Yup'ik Eskimos have traditionally eaten a diet rich in PUFAs, and were extremely active, but modernization has resulted in dramatic differences in diet and activity levels among individuals. We seek to test the hypothesis that polymorphisms in these biologically plausible candidate genes are sensitive to reduced PUFA availability and physical activity, and that these interactions ultimately influence the degree of body fat accumulation in Yup'ik Eskimos. To achieve this objective, our specific aims are: to extend our current data set of over 800 interrelated Yup'ik Eskimos to 1000 family members; to exhaustively identify SNPs in the seven candidate genes; to test these genes for association with obesity phenotypes; and to test for gene-environment and gene-gene interactions. Strengths of our approach include: (1) our ongoing access to, and excellent research partnership with, Yup'ik Eskimos; (2) large well-defined pedigrees; and (3) highly variable levels of PUFA intake and physical activity. Treatment for obesity has been only modestly successful, perhaps because the complex etiology is largely unknown. The discovery of gene-environment interactions gained from this study will further our understanding of obesity and will be relevant to future studies aimed at developing and testing interventions, and identifying novel therapeutic targets for obesity.